TOR promotes guard cell starch degradation by regulating the activity of ß-AMYLASE1 in Arabidopsis.

Starch is the main energy storage carbohydrate in plants and serves as an essential carbon storage molecule for plant metabolism and growth under changing environmental conditions. The TARGET of RAPAMYCIN (TOR) kinase is an evolutionarily conserved master regulator that integrates energy, nutrient, hormone, and stress signaling to regulate growth in all eukaryotes. Here, we demonstrate that TOR promotes guard cell starch degradation and induces stomatal opening in Arabidopsis thaliana. Starvation caused by plants growing under short photoperiod or low light photon irradiance, as well as inactivation of TOR, impaired guard cell starch degradation and stomatal opening. Sugar and TOR induce the accumulation of ß-AMYLASE1 (BAM1), which is responsible for starch degradation in guard cells. The plant steroid hormone brassinosteroid and transcription factor BRASSINAZOLE-RESISTANT1 play crucial roles in sugar-promoted expression of BAM1. Furthermore, sugar supply induced BAM1 accumulation, but TOR inactivation led to BAM1 degradation, and the effects of TOR inactivation on BAM1 degradation were abolished by the inhibition of autophagy and proteasome pathways or by phospho-mimicking mutation of BAM1 at serine-31. Such regulation of BAM1 activity by sugar-TOR signaling allows carbon availability to regulate guard cell starch metabolism and stomatal movement, ensuring optimal photosynthesis efficiency of plants.

Sodium layered oxide cathodes: properties, practicality and prospects.

Rechargeable sodium-ion batteries (SIBs) have emerged as an advanced electrochemical energy storage technology with potential to alleviate the dependence on lithium resources. Similar to Li-ion batteries, the cathode materials play a decisive role in the cost and energy output of SIBs. Among various cathode materials, Na layered transition-metal (TM) oxides have become an appealing choice owing to their facile synthesis, high Na storage capacity/voltage that are suitable for use in high-energy SIBs, and high adaptivity to the large-scale manufacture of Li layered oxide analogues. However, going from the lab to the market, the practical use of Na layered oxide cathodes is limited by the ambiguous understanding of the fundamental structure-performance correlation of cathode materials and lack of customized material design strategies to meet the diverse demands in practical storage applications. In this review, we attempt to clarify the fundamental misunderstandings by elaborating the correlations between the electron configuration of the critical capacity-contributing elements (e.g., TM cations and oxygen anion) in oxides and their influence on the Na (de)intercalation (electro)chemistry and storage properties of the cathode. Subsequently, we discuss the issues that hinder the practical use of layered oxide cathodes, their origins and the corresponding strategies to address their issues and accelerate the target-oriented research and development of cathode materials. Finally, we discuss several new Na layered cathode materials that show prospects for next-generation SIBs, including layered oxides with anion redox and high entropy and highlight the use of layered oxides as cathodes for solid-state SIBs with higher energy and safety. In summary, we aim to offer insights into the rational design of high-performance Na layered oxide cathode materials towards the practical realization of sustainable electrochemical energy storage at a low cost.

The TaSnRK1-TabHLH489 module integrates brassinosteroid and sugar signalling to regulate the grain length in bread wheat.

Regulation of grain size is a crucial strategy for improving the crop yield and is also a fundamental aspect of developmental biology. However, the underlying molecular mechanisms governing grain development in wheat remain largely unknown. In this study, we identified a wheat atypical basic helix-loop-helix (bHLH) transcription factor, TabHLH489, which is tightly associated with grain length through genome-wide association study and map-based cloning. Knockout of TabHLH489 and its homologous genes resulted in increased grain length and weight, whereas the overexpression led to decreased grain length and weight. TaSnRK1α1, the α-catalytic subunit of plant energy sensor SnRK1, interacted with and phosphorylated TabHLH489 to induce its degradation, thereby promoting wheat grain development. Sugar treatment induced TaSnRK1α1 protein accumulation while reducing TabHLH489 protein levels. Moreover, brassinosteroid (BR) promotes grain development by decreasing TabHLH489 expression through the transcription factor BRASSINAZOLE RESISTANT1 (BZR1). Importantly, natural variations in the promoter region of TabHLH489 affect the TaBZR1 binding ability, thereby influencing TabHLH489 expression. Taken together, our findings reveal that the TaSnRK1α1-TabHLH489 regulatory module integrates BR and sugar signalling to regulate grain length, presenting potential targets for enhancing grain size in wheat.

HBI transcription factor-mediated ROS homeostasis regulates nitrate signal transduction.

Nitrate is both an important nutrient and a critical signaling molecule that regulates plant metabolism, growth, and development. Although several components of the nitrate signaling pathway have been identified, the molecular mechanism of nitrate signaling remains unclear. Here, we showed that the growth-related transcription factors HOMOLOG OF BRASSINOSTEROID ENHANCED EXPRESSION2 INTERACTING WITH IBH1 (HBI1) and its three closest homologs (HBIs) positively regulate nitrate signaling in Arabidopsis thaliana. HBI1 is rapidly induced by nitrate through NLP6 and NLP7, which are master regulators of nitrate signaling. Mutations in HBIs result in the reduced effects of nitrate on plant growth and ∼22% nitrate-responsive genes no longer to be regulated by nitrate. HBIs increase the expression levels of a set of antioxidant genes to reduce the accumulation of reactive oxygen species (ROS) in plants. Nitrate treatment induces the nuclear localization of NLP7, whereas such promoting effects of nitrate are significantly impaired in the hbi-q and cat2 cat3 mutants, which accumulate high levels of H2O2. These results demonstrate that HBI-mediated ROS homeostasis regulates nitrate signal transduction through modulating the nucleocytoplasmic shuttling of NLP7. Overall, our findings reveal that nitrate treatment reduces the accumulation of H2O2, and H2O2 inhibits nitrate signaling, thereby forming a feedback regulatory loop to regulate plant growth and development.

Lipid metabolism mediates the association between body mass index change and bone mineral density: The Taizhou imaging study.

BACKGROUND: Limited research explores the impact of body mass index (BMI) change on osteoporosis, regarding the role of lipid metabolism. We aimed to cross-sectionally investigate these relationships in 820 Chinese participants aged 55-65 from the Taizhou Imaging Study. METHODS: We used the baseline data collected between 2013 and 2018. T-score was calculated by standardizing bone mineral density and was used for osteoporosis and osteopenia diagnosis. Multinomial logistic regression was used to examine the effect of BMI change on bone health status. Multivariable linear regression was employed to identify the metabolites corrected with BMI change and T-score. Exploratory factor analysis (EFA) and mediation analysis were conducted to ascertain the involvement of the metabolites. RESULTS: BMI increase served as a protective factor against osteoporosis (OR = 0.79[0.71-0.88], P-value<0.001) and osteopenia (OR = 0.88[0.82-0.95], P-value<0.001). Eighteen serum metabolites were associated with both BMI change and T-score. Specifically, high-density lipoprotein (HDL) substructures demonstrated negative correlations (ß = -0.08 to -0.06 and - 0.12 to -0.08, respectively), while very low-density lipoprotein (VLDL) substructions showed positive correlations (ß = 0.09 to 0.10 and 0.10 to 0.11, respectively). The two lipid factors (HDL and VLDL) extracted by EFA acted as mediators between BMI change and T-score (Prop. Mediated = 8.16% and 10.51%, all P-value<0.01). CONCLUSION: BMI gain among Chinese aged 55-65 is beneficial for reducing the risk of osteoporosis. The metabolism of HDL and VLDL partially mediates the effect of BMI change on bone loss. Our research offers novel insights into the prevention of osteoporosis, approached from the perspective of weight management and lipid metabolomics.

Mobility-related brain regions linking carotid intima-media thickness to specific gait performances in old age.

BACKGROUND: Gait disturbance is common in older adults with vascular diseases. However, how carotid atherosclerosis affects gait remains poorly understood. The objectives were to investigate the associations between carotid intima-media thickness and specific gait performances and explore the potential role of brain structure in mediating these associations. METHODS: A cross-sectional analysis of data from the Taizhou Imaging Study was conducted, including 707 individuals who underwent both gait and carotid ultrasound examinations. Gait assessments include the Timed-Up-and-Go test, the Tinetti test, and quantitative gait assessment using a wearable device. Quantitative parameters were summarized into independent gait domains with factor analysis. Magnetic resonance images were obtained on a 3.0-Tesla scanner, and the volumes of fifteen brain regions related to motor function (primary motor, sensorimotor), visuospatial attention (inferior posterior parietal lobules, superior posterior parietal lobules), executive control function (dorsolateral prefrontal cortex, anterior cingulate), memory (hippocampus, entorhinal cortex), motor imagery (precuneus, parahippocampus, posterior cingulated cortex), and balance (basal ganglia: pallidum, putamen, caudate, thalamus) were computed using FreeSurfer and the Desikan-Killiany atlas. Mediation analysis was conducted with carotid intima-media thickness as the predictor and mobility-related brain regions as mediators. RESULTS: Carotid intima-media thickness was found to be associated with the Timed-Up-and-Go performance (ß = 0.129, p = 0.010) as well as gait performances related to pace (ß=-0.213, p < 0.001) and symmetry (ß = 0.096, p = 0.045). Besides, gait performances were correlated with mobility-related brain regions responsible for motor, visuospatial attention, executive control, memory, and balance (all FDR < 0.05). Notably, significant regions differed depending on the gait outcomes measured. The primary motor (41.9%), sensorimotor (29.3%), visuospatial attention (inferior posterior parietal lobules, superior posterior parietal lobules) (13.8%), entorhinal cortex (36.4%), and motor imagery (precuneus, parahippocampus, posterior cingulated cortex) (27.3%) mediated the association between increased carotid intima-media thickness and poorer Timed-Up-and-Go performance. For the pace domain, the primary motor (37.5%), sensorimotor (25.8%), visuospatial attention (12.3%), entorhinal cortex (20.7%), motor imagery (24.9%), and balance (basal ganglia: pallidum, putamen, caudate, thalamus) (11.6%) acted as mediators. CONCLUSIONS: Carotid intima-media thickness is associated with gait performances, and mobility-related brain volume mediates these associations. Moreover, the distribution of brain regions regulating mobility varies in the different gait domains. Our study adds value in exploring the underlying mechanisms of gait disturbance in the aging population.

The therapeutic effect of radiotherapy combined with systemic therapy compared to radiotherapy alone in patients with simple brain metastasis after first-line treatment of limited-stage small cell lung cancer: a retrospective study.

PURPOSE: We aimed to compare the therapeutic effect of radiotherapy (RT) plus systemic therapy (ST) with RT alone in patients with simple brain metastasis (BM) after first-line treatment of limited-stage small cell lung cancer (LS-SCLC). METHODS: The patients were treated at a single center from January 2011 to January 2022. BM only without metastases to other organs was defined as simple BM. The eligible patients were divided into RT alone (monotherapy arm) and RT plus ST (combined therapy arm). Univariate and multivariate Cox proportional hazards analyses were used to examine factors associated with increased risk of extracranial progression. After 1:1 propensity score matching analysis, two groups were compared for extracranial progression-free survival (ePFS), PFS, overall survival (OS), and intracranial PFS (iPFS). RESULTS: 133 patients were identified and 100 were analyzed (monotherapy arm: n = 50, combined therapy arm: n = 50). The ePFS of the combined therapy was significantly longer than that of the monotherapy, with a median ePFS of 13.2 months (95% CI, 6.6-19.8) in combined therapy and 8.2 months (95% CI, 5.7-10.7) in monotherapy (P = 0.04). There were no statistically significant differences in PFS (P = 0.057), OS (P = 0.309), or iPFS (P = 0.448). Multifactorial analysis showed that combined therapy was independently associated with better ePFS compared with monotherapy (HR = 0.617, P = 0.034); more than 5 BMs were associated with worse ePFS compared with 1-5 BMs (HR = 1.808, P = 0.012). CONCLUSIONS: Compared with RT alone, combined therapy improves ePFS in patients with simple BM after first-line treatment of LS-SCLC. Combined therapy and 1-5 BMs reduce the risk of extracranial recurrence.

Research and Verification of a Novel Interferometry Method by Joint Processing of Downlink Pseudo-Noise Ranging and DOR Signals for Deep Space Exploration.

The remarkably long distances covered by deep space probes result in extremely weak downlink signals, which poses great challenges for ground measurement systems. In the current climate, improving the comprehensive utilization of downlink signal power to increase the detection distance or enhance the measurement accuracy is of great significance in deep space exploration. Facing this problem, we analyze the delta Differential One-way Range (ΔDOR) error budget of the X-band of the China Deep Space Network (CDSN). Then, we propose a novel interferometry method that detunes one group of DOR beacons and reuses the clock components of regenerative pseudo-code ranging signals for interferometry delay estimation. The primary advantage of this method is its ability to enhance the power utilization efficiency of downlink signals, thereby facilitating more efficient tracking and measurement without necessitating additional design requirements for deep space transponders. Finally, we analyze and verify the correctness and effectiveness of our proposed method using measured data from CDSN. Our results indicate that the proposed method can save approximately 13% of the downlink signal power and increase the detection distance by about 6.25% using typical modulation parameters. Furthermore, if the relative power of other signal components remains unchanged, the power of the DOR tone can be directly increased by more than 100%, improving the deep space exploration ability more significantly.

Pharmacokinetics and tissue distribution of vigabatrin enantiomers in rats.

Purpose: To investigate the pharmacokinetics and tissue distribution of VGB racemate and its single enantiomers, and explore the potential of clinic development for single enantiomer S-VGB. Methods: In the pharmacokinetics study, male Sprague-Dawley rats were gavaged with VGB racemate or its single enantiomers dosing 50, 100 or 200 mg/kg, and the blood samples were collected during 12 h at regular intervals. In the experiment of tissue distribution, VGB and its single enantiomers were administered intravenously dosing 200 mg/kg, and the tissues including heart, liver, spleen, lung and kidney, eyes, hippocampus, and prefrontal cortex were separated at different times. The concentrations of R-VGB and S-VGB in the plasma and tissues were measured using HPLC. Results: Both S-VGB and R-VGB could be detected in the plasma of rats administered with VGB racemate, reaching Cmax at approximately 0.5 h with t1/2 2-3 h. There was no significant pharmacokinetic difference between the two enantiomers when VGB racemate was given 200 mg/kg and 100 mg/kg. However, when given at the dose of 50 mg/kg, S-VGB presented a shorter t1/2 and a higher Cl/F than R-VGB, indicating a faster metabolism of S-VGB. Furthermore, when single enantiomer was administered respectively, S-VGB presented a slower metabolism than R-VGB, as indicated by a longer t1/2 and MRT but a lower Cmax. Moreover, compared with the VGB racemate, the single enantiomers S-VGB and R-VGB had shorter t1/2 and MRT, higher Cmax and AUC/D, and lower Vz/F and Cl/F, indicating the stronger oral absorption and faster metabolism of single enantiomer. In addition, regardless of VGB racemate administration or single enantiomer administration, S-VGB and R-VGB had similar characteristics in tissue distribution, and the content of S-VGB in hippocampus, prefrontal cortex and liver was much higher than that of R-VGB. Conclusions: Although there is no transformation between S-VGB and R-VGB in vivo, those two enantiomers display certain disparities in the pharmacokinetics and tissue distribution, and interact with each other. These findings might be a possible interpretation for the pharmacological and toxic effects of VGB and a potential direction for the development and optimization of the single enantiomer S-VGB.

Approaching Sustainable Lithium-Ion Batteries through Voltage-Responsive Smart Prelithiation Separator with Surface-Engineered Sacrificial Lithium Agents.

The surge in lithium-ion batteries has heightened concerns regarding metal resource depletion and the environmental impact of spent batteries. Battery recycling has become paramount globally, but conventional techniques, while effective at extracting transition metals like cobalt and nickel from cathodes, often overlook widely used spent LiFePO4 due to its abundant and low-cost iron content. Direct regeneration, a promising approach for restoring deteriorated cathodes, is hindered by practicality and cost issues despite successful methods like solid-state sintering. Hence, a smart prelithiation separator based on surface-engineered sacrificial lithium agents is proposed. Benefiting from the synergistic anionic and cationic redox, the prelithiation separator can intelligently release or intake active lithium via voltage regulation. The staged lithium replenishment strategy was implemented, successfully restoring spent LiFePO4's capacity to 163.7 mAh g-1 and a doubled life. Simultaneously, the separator can absorb excess active lithium up to approximately 600 mAh g-1 below 2.5 V to prevent over-lithiation of the cathode This innovative, straightforward, and cost-effective strategy paves the way for the direct regeneration of spent batteries, expanding the possibilities in the realm of lithium-ion battery recycling.

Health and economic impact of improved glucose, blood pressure and lipid control among German adults with type 2 diabetes: a modelling study.

AIMS/HYPOTHESIS: The aim of this study was to estimate the long-term health and economic consequences of improved risk factor control in German adults with type 2 diabetes. METHODS: We used the UK Prospective Diabetes Study Outcomes Model 2 to project the patient-level health outcomes and healthcare costs of people with type 2 diabetes in Germany over 5, 10 and 30 years. We parameterised the model using the best available data on population characteristics, healthcare costs and health-related quality of life from German studies. The modelled scenarios were: (1) a permanent reduction of HbA1c by 5.5 mmol/mol (0.5%), of systolic BP (SBP) by 10 mmHg, or of LDL-cholesterol by 0.26 mmol/l in all patients, and (2) achievement of guideline care recommendations for HbA1c (≤53 mmol/mol [7%]), SBP (≤140 mmHg) or LDL-cholesterol (≤2.6 mmol/l) in patients who do not meet the recommendations. We calculated nationwide estimates using age- and sex-specific quality-adjusted life year (QALY) and cost estimates, type 2 diabetes prevalence and population size. RESULTS: Over 10 years, a permanent reduction of HbA1c by 5.5 mmol/mol (0.5%), SBP by 10 mmHg or LDL-cholesterol by 0.26 mmol/l led to per-person savings in healthcare expenditures of €121, €238 and €34, and 0.01, 0.02 and 0.015 QALYs gained, respectively. Achieving guideline care recommendations for HbA1c, SBP or LDL-cholesterol could reduce healthcare expenditure by €451, €507 and €327 and gained 0.03, 0.05 and 0.06 additional QALYs in individuals who did not meet the recommendations. Nationally, achieving guideline care recommendations for HbA1c, SBP and LDL-cholesterol could reduce healthcare costs by over €1.9 billion. CONCLUSIONS/INTERPRETATION: Sustained improvements in HbA1c, SBP and LDL-cholesterol control among diabetes patients in Germany can lead to substantial health benefits and reduce healthcare expenditures.

Messenger RNA Coronavirus Disease 2019 (COVID-19) Vaccination With BNT162b2 Increased Risk of Bell's Palsy: A Nested Case-Control and Self-Controlled Case Series Study.

BACKGROUND: Observable symptoms of Bell's palsy following vaccinations arouse concern over the safety profiles of novel coronavirus disease 2019 (COVID-19) vaccines. However, there are only inconclusive findings on Bell's palsy following messenger (mRNA) COVID-19 vaccination. This study aims to update the previous analyses on the risk of Bell's palsy following mRNA (BNT162b2) COVID-19 vaccination. METHODS: This study included cases aged ≥16 years with a new diagnosis of Bell's palsy within 28 days after BNT162b2 vaccinations from the population-based electronic health records in Hong Kong. Nested case-control and self-controlled case series (SCCS) analyses were used, where the association between Bell's palsy and BNT162b2 was evaluated using conditional logistic and Poisson regression, respectively. RESULTS: Totally 54 individuals were newly diagnosed with Bell's palsy after BNT162b2 vaccinations. The incidence of Bell's palsy was 1.58 (95% confidence interval [CI], 1.19-2.07) per 100 000 doses administered. The nested case-control analysis showed significant association between BNT162b2 vaccinations and Bell's palsy (adjusted odds ratio [aOR], 1.543; 95% CI, 1.123-2.121), with up to 1.112 excess events per 100 000 people who received 2 doses of BNT162b2. An increased risk of Bell's palsy was observed during the first 14 days after the second dose of BNT162b2 in both nested case-control (aOR, 2.325; 95% CI, 1.414-3.821) and SCCS analysis (adjusted incidence rate ratio, 2.44; 95% CI, 1.32-4.50). CONCLUSIONS: There was an overall increased risk of Bell's palsy following BNT162b2 vaccination, particularly within the first 14 days after the second dose, but the absolute risk was very low.

Refined Electrolyte and Interfacial Chemistry toward Realization of High-Energy Anode-Free Rechargeable Sodium Batteries.

Anode-free rechargeable sodium batteries represent one of the ultimate choices for the 'beyond-lithium' electrochemical storage technology with high energy. Operated based on the sole use of active Na ions from the cathode, the anode-free battery is usually reported with quite a limited cycle life due to unstable electrolyte chemistry that hinders efficient Na plating/stripping at the anode and high-voltage operation of the layered oxide cathode. A rational design of the electrolyte toward improving its compatibility with the electrodes is key to realize the battery. Here, we show that by refining the volume ratio of two conventional linear ether solvents, a binary electrolyte forms a cation solvation structure that facilitates flat, dendrite-free, planar growth of Na metal on the anode current collector and that is adaptive to high-voltage Na (de)intercalation of P2-/O3-type layered oxide cathodes and oxidative decomposition of the Na2C2O4 supplement. Inorganic fluorides, such as NaF, show a major influence on the electroplating pattern of Na metal and effective passivation of plated metal at the anode-electrolyte interface. Anode-free batteries based on the refined electrolyte have demonstrated high coulombic efficiency, long cycle life, and the ability to claim a cell-level specific energy of >300 Wh/kg.

Metagenomic association analysis of cognitive impairment in community-dwelling older adults.

The gut microbiota is reportedly involved in neurodegenerative disorders, and exploration of differences in the gut microbiota in different cognitive status could provide clues for early detection and intervention in cognitive impairment. Here, we used data from the Taizhou Imaging Study (N = 516), a community-based cohort, to compare the overall structure of the gut microbiota at the species level through metagenomic sequencing, and to explore associations with cognition. Interestingly, bacteria capable of producing short-chain fatty acids (SCFAs), such as Bacteroides massiliensis, Bifidobacterium pseudocatenulatum, Fusicatenibacter saccharivorans and Eggerthella lenta, that can biotransform polyphenols, were positively associated with better cognitive performance (p < 0.05). Although Diallister invisus and Streptococcus gordonii were not obviously related to cognition, the former was dominant in individuals with mild cognitive impairment (MCI), while the later was more abundant in cognitively normal (CN) than MCI groups, and positively associated with cognitive performance (p < 0.05). Functional analysis further supported a potential role of SCFAs and lactic acid in the association between the gut microbiota and cognition. The significant associations persisted after accounting for dietary patterns. Collectively, our results demonstrate an association between the gut microbiota and cognition in the general population, indicating a potential role in cognitive impairment. The findings provide clues for microbiome biomarkers of dementia, and insight for the prevention and treatment of dementia.

Brassinosteroid and Hydrogen Peroxide Interdependently Induce Stomatal Opening by Promoting Guard Cell Starch Degradation.

Starch is the major storage carbohydrate in plants and functions in buffering carbon and energy availability for plant fitness with challenging environmental conditions. The timing and extent of starch degradation appear to be determined by diverse hormonal and environmental signals; however, our understanding of the regulation of starch metabolism is fragmentary. Here, we demonstrate that the phytohormone brassinosteroid (BR) and redox signal hydrogen peroxide (H2O2) induce the breakdown of starch in guard cells, which promotes stomatal opening. The BR-insensitive mutant bri1-116 accumulated high levels of starch in guard cells, impairing stomatal opening in response to light. The gain-of-function mutant bzr1-1D suppressed the starch excess phenotype of bri1-116, thereby promoting stomatal opening. BRASSINAZOLE-RESISTANT1 (BZR1) interacts with the basic leucine zipper transcription factor G-BOX BINDING FACTOR2 (GBF2) to promote the expression of ß-AMYLASE1 (BAM1), which is responsible for starch degradation in guard cells. H2O2 induces BZR1 oxidation, enhancing the interaction between BZR1 and GBF2 to increase BAM1 transcription. Mutations in BAM1 lead to starch accumulation and reduce the effects of BR and H2O2 on stomatal opening. Overall, this study uncovers the critical roles of BR and H2O2 in regulating guard cell starch metabolism and stomatal opening.

The miR396-GRFs Module Mediates the Prevention of Photo-oxidative Damage by Brassinosteroids during Seedling De-Etiolation in Arabidopsis.

The switch from dark- to light-mediated development is critical for the survival and growth of seedlings, but the underlying regulatory mechanisms are incomplete. Here, we show that the steroids phytohormone brassinosteroids play crucial roles during this developmental transition by regulating chlorophyll biosynthesis to promote greening of etiolated seedlings upon light exposure. Etiolated seedlings of the brassinosteroids-deficient det2-1 (de-etiolated2) mutant accumulated excess protochlorophyllide, resulting in photo-oxidative damage upon exposure to light. Conversely, the gain-of-function mutant bzr1-1D (brassinazole-resistant 1-1D) suppressed the protochlorophyllide accumulation of det2-1, thereby promoting greening of etiolated seedlings. Genetic analysis indicated that phytochrome-interacting factors (PIFs) were required for BZR1-mediated seedling greening. Furthermore, we reveal that GROWTH REGULATING FACTOR 7 (GRF7) and GRF8 are induced by BZR1 and PIF4 to repress chlorophyll biosynthesis and promote seedling greening. Suppression of GRFs function by overexpressing microRNA396a caused an accumulation of protochlorophyllide in the dark and severe photobleaching upon light exposure. Additionally, BZR1, PIF4, and GRF7 interact with each other and precisely regulate the expression of chlorophyll biosynthetic genes. Our findings reveal an essential role for BRs in promoting seedling development and survival during the initial emergence of seedlings from subterranean darkness into sunlight.

Causal associations between gut microbiota and sepsis: A two-sample Mendelian randomization study.

BACKGROUND: Targeting the gut microbiota may become a new therapeutic to prevent and treat sepsis. Nonetheless, the causal relationship between specific intestinal flora and sepsis is still unclear. METHODS: A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genome-wide association study (n = 18,340). The summary statistics of sepsis were obtained from the UK Biobank (n = 486,484). Inverse-variance weighted, weighted median and MR-Egger were used to examine the causal association between gut microbiota and sepsis. Cochrane's Q test, MR-Egger intercept test, MR-PRESSO Global test and Rucker's Q'-test were used for sensitivity analyses. The leave-one method was used for testing the stability of MR results, and Bonferroni-corrected was used to test the strength of the causal relationship between exposure and outcome. RESULTS: Nine intestinal microflora were found causally associated with sepsis, and 11 intestinal microflora were causally associated with 28-day death in sepsis. Among them, Order Victivallales had a strong causality with lower risk of sepsis (OR = 0.86, 95% CI: 0.78-0.94, p = .00165) and lower 28-day mortality of sepsis (OR = 0.68, 95% CI: 0.53-0.87, p = .00179) after Bonferroni-corrected test. No pleiotropy was detected. CONCLUSIONS: Through the two-sample MR analysis, we identified the specific intestinal flora that had a causal relationship with the risk and prognosis of sepsis at the level of gene prediction, which may provide helpful biomarkers for early disease diagnosis and potential therapeutic targets for sepsis.

Prevalence of impaired awareness of hypoglycaemia in people with diabetes mellitus: A systematic review and meta-analysis from 21 countries and regions.

AIMS: Impaired awareness of hypoglycaemia (IAH) is a complication of glucose-lowering therapies for diabetes. The purpose of this review was to estimate the pooled prevalence of IAH and unawareness of hypoglycaemia (UAH). METHODS: We searched the major databases from inception to 8 August 2022 and included all cross-sectional and cohort studies reporting IAH prevalence in people with diabetes. A random-effects model was used to pool effect values. Subgroup analysis and meta-regression were used to identify study-level characteristics affecting prevalence. RESULTS: Sixty-two studies from 21 countries published between 2000 and 2022 were included, with 39,180 participants (type 1 diabetes: 19,304 vs. Type 2 diabetes: 14,650). The pooled prevalence was 23.2% (95% CI: 18.4%-29.3%) via the Clarke questionnaire, 26.2% (95% CI: 22.9%-29.9%) via the Gold score, and 58.5% (95% CI: 53.0%-64.6%) via the Pedersen-Bjergaard method, all from studies classified as presenting a moderate and low risk of bias. The prevalence of IAH was generally higher in people with type 1 diabetes than in those with type 2 diabetes and lowest in Europe. Meta-regression results show that the duration of diabetes was a factor influencing the prevalence of IAH. The prevalence of UAH by the Pedersen-Bjergaard method was 17.6 (95% CI: 14.9%-20.3%). CONCLUSIONS: IAH is a prevalent risk event among people with type 1 and type 2 diabetes, showing clinical heterogeneity and regional variability. UAH, an adverse progression of IAH, is also a serious burden. More primary research on the prevalence of IAH is needed in areas with a high diabetes burden.

Treatment with methylphenidate and the risk of fractures among children and young people: A systematic review and self-controlled case series study.

AIMS: Animal studies suggest that methylphenidate treatment for around 3 months may lead to less mineralized and weaker appendicular bones. A systematic review was conducted to summarize the evidence from observational studies, and a self-controlled case series study was used to compare the risk before and after treatment initiation. METHODS: Literature search was conducted using PubMed, Embase and the Cochrane Library to identify observational studies on methylphenidate and fractures. We also conducted a self-controlled case series study with individuals aged 5-24 years who received methylphenidate treatment and experienced fractures from 2001 to 2020 in Hong Kong. Incidence rate ratios and 95% confidence intervals were calculated by comparing the incidence rate in the methylphenidate-exposed period compared with nonexposed period. RESULTS: Six cohort studies and 2 case-control studies were included in the systematic review. For all-cause fractures, studies found a 39-74% lower risk in treated-attention deficit hyperactivity disorder (ADHD) group compared with untreated ADHD but no difference between stimulants and nonstimulants. Differences between sexes and treatment duration were also found-significant results were shown in males and those with longer treatment duration. Among 43 841 individuals with ADHD medication before the year 2020, 2023 were included in the self-controlled case series analysis. The risks of fractures were lower by 32-41% in different treatment periods when compared with 6 months before treatment initiation. CONCLUSION: Methylphenidate treatment may lower the risk of all-cause fractures from both study designs; however, further evidence is needed about the treatment duration and sex effect. Conclusions on stress fractures are not yet established, and further research is required.

A feasible method to evaluate fetal palate: sequential sector-scan through oral fissure.

BACKGROUND: Prenatal diagnosis of cleft palate is still challenging. To describe a practical and efficient method, sequential sector-scan through oral fissure (SSTOF), to evaluate palate. METHODS: According to the characteristics of the fetal oral anatomy and ultrasonic directivity, we designed a practical method, sequential sector-scan through oral fissure, to evaluate the fetal palate, and the approach was verified efficiently by following up results of those fetuses with orofacial cleft who were induced because of their accompanied lethal malformations. Then, the 7098 fetuses were evaluated using sequential sector-scan through oral fissure. Fetuses were followed up after birth or induction to validate and analyze prenatal diagnosis. RESULT: According to the scanning design, sequential sector-scan through oral fissure was performed successfully from the soft palate to the upper alveolar ridge in induced labor fetuses, and the structures were displayed clearly. Among 7098 fetuses, satisfactory images were obtained for 6885 fetuses and the remaining 213 fetuses' images were unsatisfactory because of fetuses' positions and pregnant women with high BMI. Among 6885 fetuses, 31cases were diagnosed CLP or CP, which were confirmed after delivery or termination. There were no missing cases. CONCLUSIONS: SSTOF is a practical and efficient method to diagnose cleft palate, which might be applied to evaluate the fetal palate in prenatal diagnosis.